PM_2.5-induced ferroptosis by Nrf2/Hmox1 signaling pathway led to inflammation in microglia

Particulate matter (PM) has been a dominant contributor to air contamination, which will enter the central nervous system (CNS), causing neurotoxicity. However, the biological mechanism is poorly identified. In this study, C57BL/6J mice were applied to evaluate the neurotoxicity of collected fine particulate matter (PM_2.5), via oropharyngeal aspiration at two ambient equivalent concentrations. The Y-maze results showed that PM_2.5 exposure in mice would lead to the damage in hippocampal-dependent working memory. In addition, cell neuroinflammation, microglial activation were detected in hippocampus of PM_2.5-exposure mice. To confirm the underlying mechanism, the microarray assay was conducted to screen the differentially expressed genes (DEGs) in microglia after PM_2.5 exposure, and the results indicated the enrichment of DEGs in ferroptosis pathways. Furthermore, Heme oxygenase-1 (Hmox1) was found to be one of the most remarkably upregulated genes after PM_2.5 exposure for 24 h. And PM_2.5 exposure induced ferroptosis with iron accumulation through heme degradation by Nrf2-mediated Hmox1 upregulation, which could be eliminated by Nrf2-inhibition. Meanwhile, Hmox1 antagonist zinc protoporphyrin IX (ZnPP) could protect BV2 cells from ferroptosis. The results taken together indicated that PM_2.5 resulted in the ferroptosis by causing iron overload through Nrf2/Hmox1 signaling pathway, which could account for the inflammation in microglia.